tbuckley/cabot-search huggingface dataset:
What is the future for covid drugs and treatments?
Authors: Mun-Keat Looi
Journal: BMJ (2023)

What is the future for covid drugs and treatments?Looi reports on where research is focused and what's missing from the covid treatment pipeline Mun-Keat Looi international features editorWhat new treatments or approaches are on the horizon?It's not so much about "new" treatments as continuing research to prove effectiveness of drugs we already know work in practice, says Janet Diaz, who leads clinical management at the World Health Organization's Health Emergencies Programme."I think we're still seeing a mixture of different types of products in regard to the immunomodulation type," she says."We have corticosteroids, IL-6 receptor tocilizumab, and then Janus kinase inhibitors, baricitinib. 1 If we can really improve access to those and get clinicians to integrate them into covid-19 care pathways for severe and critical cases in hospitals, I think that would be a big advancement.
Effects of a 16-week home-based exercise training programme on health-related quality of life, functional capacity, and persistent symptoms in survivors of severe/critical COVID-19: a randomised controlled trial
Authors: Igor Longobardi, Karla Goessler, Gersiel Nascimento de Oliveira Júnior, Danilo Marcelo Leite do Prado, Jhonnatan Vasconcelos Pereira Santos, Matheus Molina Meletti, Danieli Castro Oliveira de Andrade, Saulo Gil, João Antonio Spott de Oliveira Boza, Fernanda Rodrigues Lima, Bruno Gualano, Hamilton Roschel
Journal: British Journal of Sports Medicine (2023)

Long-lasting effects of COVID-19 may include cardiovascular, respiratory, skeletal muscle, metabolic, psychological disorders and persistent symptoms that can impair health-related quality of life (HRQoL). We investigated the effects of a home-based exercise training (HBET) programme on HRQoL and health-related outcomes in survivors of severe/critical COVID-19.This was a single-centre, single-blinded, parallel-group, randomised controlled trial. Fifty survivors of severe/critical COVID-19 (5±1 months after intensive care unit discharge) were randomly allocated (1:1) to either a 3 times a week (~60-80 min/session), semi-supervised, individualised, HBET programme or standard of care (CONTROL). Changes in HRQoL were evaluated through the 36-Item Short-Form Health Survey, and physical component summary was predetermined as the primary outcome. Secondary outcomes included cardiorespiratory fitness, pulmonary function, functional capacity, body composition and persistent symptoms. Assessments were performed at baseline and after 16 weeks of intervention. Statistical analysis followed intention-to-treat principles.After the intervention, HBET showed greater HRQoL score than CONTROL in the physical component summary (estimated mean difference, EMD: 16.8 points; 95% CI 5.8 to 27.9; effect size, ES: 0.74), physical functioning (EMD: 22.5 points, 95% CI 6.1 to 42.9, ES: 0.83), general health (EMD: 17.4 points, 95% CI 1.8 to 33.1, ES: 0.73) and vitality (EMD: 15.1 points, 95% CI 0.2 to 30.1, ES: 0.49) domains. 30-second sit-to-stand (EMD: 2.38 reps, 95% CI 0.01 to 4.76, ES: 0.86), and muscle weakness and myalgia were also improved in HBET compared with CONTROL (p<0.05). No significant differences were seen in the remaining variables. There were no adverse events.HBET is an effective and safe intervention to improve physical domains of HRQoL, functional capacity and persistent symptoms in survivors of severe/critical COVID-19.NCT04615052.
Pathogenesis of autoimmune disease
Authors: David S. Pisetsky
Journal: Nature Reviews Nephrology (2023)

Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur widely and affect individuals of all ages, especially women. Among these diseases, the most prominent immunological manifestation is the production of autoantibodies, which provide valuable biomarkers for diagnosis, classification and disease activity. Although T cells have a key role in pathogenesis, they are technically more difficult to assay. In general, autoimmune disease results from an interplay between a genetic predisposition and environmental factors. Genetic predisposition to autoimmunity is complex and can involve multiple genes that regulate the function of immune cell populations. Less frequently, autoimmunity can result from single-gene mutations that affect key regulatory pathways. Infection seems to be a common trigger for autoimmune disease, although the microbiota can also influence pathogenesis. As shown in seminal studies, patients may express autoantibodies many years before the appearance of clinical or laboratory signs of disease — a period called pre-clinical autoimmunity. Monitoring autoantibody expression in at-risk populations may therefore enable early detection and the initiation of therapy to prevent or attenuate tissue damage. Autoimmunity may not be static, however, and remission can be achieved by some patients treated with current agents. Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal host constituents. This Review provides an overview of the basis of autoimmune disease with a focus on autoantibodies, given their valuable role as markers for diagnosis, classification and of disease activity.
OncoVEX<sup>mGM-CSF</sup>expands tumor antigen-specific CD8+ T-cell response in preclinical models
Authors: Juan Estrada, Jinghui Zhan, Petia Mitchell, Jonathan Werner, Pedro J Beltran, Jason DeVoss, Jing Qing, Keegan S Cooke
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) have demonstrated clinical efficacy in advanced melanoma, but only a subset of patients with inflamed tumors are responsive. Talimogene laherparepvec (T-VEC), a modified herpes simplex virus type 1 (HSV-1) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), is a first-in-class oncolytic immunotherapy approved for the treatment of melanoma and has been shown to inflame the tumor microenvironment. To evaluate the potential and mechanisms of T-VEC to elicit systemic antitumor immunity and overcome resistance to checkpoint inhibitors in murine tumor models, OncoVEX mGM-CSF was developed similarly to T-VEC, except the human GM-CSF transgene was replaced with murine GM-CSF. Previous work had demonstrated that OncoVEX mGM-CSF generated systemic antitumor immunity dependent on CD8+ T cells in an immune checkpoint-sensitive tumor cell model. Methods A novel B16F10 syngeneic tumor model with both HSV-1−permissive subcutaneous tumors and HSV-1−refractory experimental lung metastasis was used to study the local and systemic effects of OncoVEX mGM-CSF treatment alone or in combination with checkpoint inhibitors. Results Intratumoral injection of OncoVEX mGM-CSF in combination with an anti-CTLA-4 or anti-PD-1 blocking antibody led to increased tumor growth inhibition, a reduction in the number of lung metastases, and prolonged animal survival. OncoVEX mGM-CSF induced both neoantigen-specific and tumor antigen-specific T-cell responses. Furthermore, cured mice from the combination treatment of OncoVEX mGM-CSF and anti-CTLA-4 antibody rejected tumor rechallenges. Conclusions These data support the concept that T-VEC and checkpoint inhibition may be an effective combination to treat patients with advanced melanoma.
Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years
Authors: Mauro Maccarrone, Vincenzo Di Marzo, Jürg Gertsch, Uwe Grether, Allyn C. Howlett, Tian Hua, Alexandros Makriyannis, Daniele Piomelli, Natsuo Ueda, Mario van der Stelt
Journal: Pharmacological Reviews (2023)

The cannabis derivative marijuana is the most widely used recreational drug in the Western world and is consumed by an estimated 83 million individuals (∼3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the United States and worldwide. Compelling research evidence and the Food and Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ
Assessment of Disruptive Life Events for Individuals Diagnosed With Schizophrenia or Bipolar I Disorder Using Data From a Consumer Credit Reporting Agency
Authors: Claudia L. Nau, Jordan M. Braciszewski, Rebecca C. Rossom, Robert B. Penfold, Karen J. Coleman, Gregory E. Simon, Benjamin Hong, Ariadna Padilla, Rebecca K. Butler, Aiyu Chen, Heidi C. Waters
Journal: JAMA Psychiatry (2023)

There is a dearth of population-level data on major disruptive life events (defined here as arrests by a legal authority, address changes, bankruptcy, lien, and judgment filings) for patients with bipolar I disorder (BPI) or schizophrenia, which has limited studies on mental health and treatment outcomes.To conduct a population-level study on disruptive life events by using publicly available data on disruptive life events, aggregated by a consumer credit reporting agency in conjunction with electronic health record (EHR) data.This study used EHR data from 2 large, integrated health care systems, Kaiser Permanente Southern California and Henry Ford Health. Cohorts of patients diagnosed from 2007 to 2019 with BPI or schizophrenia were matched 1:1 by age at analysis, age at diagnosis (if applicable), sex, race and ethnicity, and Medicaid status to (1) an active comparison group with diagnoses of major depressive disorder (MDD) and (2) a general health (GH) cohort without diagnoses of BPI, schizophrenia, or MDD. Patients with diagnoses of BPI or schizophrenia and their respective comparison cohorts were matched to public records data aggregated by a consumer credit reporting agency (98% match rate). Analysis took place between November 2020 and December 2022.The differences in the occurrence of disruptive life events among patients with BPI or schizophrenia and their comparison groups.Of 46 167 patients, 30 008 (65%) had BPI (mean [SD] age, 42.6 [14.2] years) and 16 159 (35%) had schizophrenia (mean [SD], 41.4 [15.1] years). The majoriy of patients were White (30 167 [65%]). In addition, 18 500 patients with BPI (62%) and 6552 patients with schizophrenia (41%) were female. Patients with BPI were more likely to change addresses than patients in either comparison cohort (with the incidence ratio being as high as 1.25 [95% CI, 1.23-1.28]) when compared with GH cohort. Patients with BPI were also more likely to experience any of the financial disruptive life events with odds ratio ranging from 1.15 [95% CI, 1.07-1.24] to 1.50 [95% CI, 1.42-1.58]). The largest differences in disruptive life events were seen in arrests of patients with either BPI or schizophrenia compared with GH peers (3.27 [95% CI, 2.84-3.78] and 3.04 [95% CI, 2.57-3.59], respectively). Patients with schizophrenia had fewer address changes and were less likely to experience a financial event than their matched comparison cohorts.This study demonstrated that data aggregated by a consumer credit reporting agency can support population-level studies on disruptive life events among patients with BPI or schizophrenia.
A review and meta-analysis: Cross-tissue telomere length correlations in healthy humans
Authors: Lauren W.Y. McLester-Davis, Pedro Estrada, Waylon J. Hastings, Leila A. Kataria, Noelle A. Martin, Joshua T. Siebeneicher, Renee I. Tristano, Celia V. Mayne, Raquel P. Horlick, Samantha S. O’Connell, Stacy S. Drury
Journal: Ageing Research Reviews (2023)
HTLV-1 bZIP Factor-Induced Reprogramming of Lactate Metabolism and Epigenetic Status Promote Leukemic Cell Expansion
Authors: Kosuke Toyoda, Jun-ichirou Yasunaga, Takafumi Shichijo, Yuichiro Arima, Kenichi Tsujita, Azusa Tanaka, Tarig Salah, Wenyi Zhang, Osama Hussein, Miyu Sonoda, Miho Watanabe, Daisuke Kurita, Kazutaka Nakashima, Kyohei Yamada, Hiroaki Miyoshi, Koichi Ohshima, Masao Matsuoka
Journal: Blood Cancer Discovery (2023)

Abstract Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is typically secreted from cancer cells because its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminishes the development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreases the growth of ATL cells in vitro and in vivo. MCT1/4 expression is positively correlated with TAp73 in many cancers, and MCT1/4 upregulation is associated with dismal prognosis. Activation of the TAp73–MCT1/4 pathway could be a common mechanism contributing to cancer metabolism. Significance: An antisense gene encoded in HTLV-1, HBZ, reprograms lactate metabolism and epigenetic modification by inducing TAp73 in virus-positive leukemic cells. A positive correlation between TAp73 and its target genes is also observed in many other cancer cells, suggesting that this is a common mechanism for cellular oncogenesis. This article is featured in Selected Articles from This Issue, p. 337
Automated Assessment of Cardiac Systolic Function From Coronary Angiograms With Video-Based Artificial Intelligence Algorithms
Authors: Robert Avram, Joshua P. Barrios, Sean Abreau, Cheng Yee Goh, Zeeshan Ahmed, Kevin Chung, Derek Y. So, Jeffrey E. Olgin, Geoffrey H. Tison
Journal: JAMA Cardiology (2023)

Importance Understanding left ventricular ejection fraction (LVEF) during coronary angiography can assist in disease management. Objective To develop an automated approach to predict LVEF from left coronary angiograms. Design, Setting, and Participants This was a cross-sectional study with external validation using patient data from December 12, 2012, to December 31, 2019, from the University of California, San Francisco (UCSF). Data were randomly split into training, development, and test data sets. External validation data were obtained from the University of Ottawa Heart Institute. Included in the analysis were all patients 18 years or older who received a coronary angiogram and transthoracic echocardiogram (TTE) within 3 months before or 1 month after the angiogram. Exposure A video-based deep neural network (DNN) called CathEF was used to discriminate (binary) reduced LVEF (≤40%) and to predict (continuous) LVEF percentage from standard angiogram videos of the left coronary artery. Guided class-discriminative gradient class activation mapping (GradCAM) was applied to visualize pixels in angiograms that contributed most to DNN LVEF prediction. Results A total of 4042 adult angiograms with corresponding TTE LVEF from 3679 UCSF patients were included in the analysis. Mean (SD) patient age was 64.3 (13.3) years, and 2212 patients were male (65%). In the UCSF test data set (n = 813), the video-based DNN discriminated (binary) reduced LVEF (≤40%) with an area under the receiver operating characteristic curve (AUROC) of 0.911 (95% CI, 0.887-0.934); diagnostic odds ratio for reduced LVEF was 22.7 (95% CI, 14.0-37.0). DNN-predicted continuous LVEF had a mean absolute error (MAE) of 8.5% (95% CI, 8.1%-9.0%) compared with TTE LVEF. Although DNN-predicted continuous LVEF differed 5% or less compared with TTE LVEF in 38.0% (309 of 813) of test data set studies, differences greater than 15% were observed in 15.2% (124 of 813). In external validation (n = 776), video-based DNN discriminated (binary) reduced LVEF (≤40%) with an AUROC of 0.906 (95% CI, 0.881-0.931), and DNN-predicted continuous LVEF had an MAE of 7.0% (95% CI, 6.6%-7.4%). Video-based DNN tended to overestimate low LVEFs and underestimate high LVEFs. Video-based DNN performance was consistent across sex, body mass index, low estimated glomerular filtration rate (≤45), presence of acute coronary syndromes, obstructive coronary artery disease, and left ventricular hypertrophy. Conclusion and relevance This cross-sectional study represents an early demonstration of estimating LVEF from standard angiogram videos of the left coronary artery using video-based DNNs. Further research can improve accuracy and reduce the variability of DNNs to maximize their clinical utility.
Fighting and Penalty Minutes Associated With Long-term Mortality Among National Hockey League Players, 1967 to 2022
Authors: Charles A. Popkin, Cole R. Morrissette, Thomas A. Fortney, Kyle L. McCormick, Prakash Gorroochurn, Michael J. Stuart
Journal: JAMA Network Open (2023)

Importance National Hockey League (NHL) players are exposed to frequent head trauma. The long-term consequences of repetitive brain injury, especially for players who frequently engage in fighting, remains unknown. Objective To investigate the mortality rates and causes of death among NHL enforcers with more career fights and penalty minutes as compared with matched controls. Design, Setting, and Participants This matched cohort study examined 6039 NHL players who participated in at least 1 game in the seasons between October 11, 1967, and April 29, 2022, using official NHL data. Cohorts designated as enforcer-fighter (E-F) and enforcer-penalties (E-P) were selected. The E-F cohort consisted of players who participated in 50 or more career fights (n = 331). The E-P cohort included players with 3 or more penalty minutes per game (n = 183). Control-matched NHL players were identified for each E-F player (control-fighter [C-F]) (n = 331) and each E-P player (control-penalties [C-P]) (n = 183). Exposures Fighting and penalty minutes were both used as proxies for head trauma exposure. Players with significantly increased exposure to fighting and penalties (E-F and E-P cohorts) were compared with NHL players with less frequent exposure to head trauma (C-F and C-P cohorts). Main Outcomes and Measures Mortality rates and age at death of the enforcer and control cohorts, and their causes of death using data obtained from publicly available sources such as online and national news sources, including NHL.com. Results Among the 6039 NHL players identified (mean [SD] age, 47.1 [15.2] years), the mean (SD) number of fights was 9.7 (24.5). The mortality rates of E-F and C-F players (13 [3.9%] vs 14 [4.2%], respectively; P = .84) or E-P and C-P players (13 [7.1.%] vs 10 [5.5%]; P = .34) were not significantly different. The mean (SD) age at death was 10 years younger for E-F players (47.5 [13.8] years) and E-P players (45.2 [10.5] years) compared with C-F players (57.5 [7.1] years) and C-P players (55.2 [8.4] years). There was a difference in causes of death between the control and enforcer players (2 neurodegenerative disorders, 2 drug overdoses, 3 suicides, and 4 vehicular crashes among enforcers vs 1 motor vehicle crash among controls; P = .03), with enforcers dying at higher rates of overdose (2 of 21 [9.5%] vs 0 of 24) and suicide (3 of 21 [14.3%] vs 0 of 24) ( P = .02). Conclusions and Relevance The findings of this matched cohort study indicate that there is no difference in overall mortality rates between NHL enforcers and controls. However, being an enforcer was associated with dying approximately 10 years earlier and more frequently of suicide and drug overdose.
Analysis of Body Mass Index in Early and Middle Adulthood and Estimated Risk of Gastrointestinal Cancer
Authors: Holli A. Loomans-Kropp, Asad Umar
Journal: JAMA Network Open (2023)

Importance In a population with significantly increasing rates of individuals with overweight or obesity, understanding the association of obesity with long-term disease risk, such as cancer, is necessary to improve public health. Objective To investigate the association between body mass index (BMI) and gastrointestinal (GI) cancer risk (colorectal cancer [CRC] and noncolorectal GI cancer) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Design, Setting, and Participants This retrospective cohort study was a secondary analysis of data from the PLCO Cancer Screening Trial. Participants aged 55 to 74 years were enrolled and randomized to the intervention (screening group) or control group at 10 screening centers between November 8, 1993, and July 2, 2001. The initial analysis of PLCO Cancer Screening Trial data occurred after 13 years of follow-up or December 31, 2009, whichever came first. Participants were reconsented in 2011 and either continued follow-up or refused additional follow-up. For those who reconsented, follow-up for incident cancers continued until December 31, 2014, or death, whichever occurred first. Data analysis for this secondary analysis was performed from April 2022 through November 2022. Exposures Body mass index and aspirin use, defined as the frequency of use of aspirin or aspirin-containing substances in the last 12 months. Main Outcomes and Measures The primary outcomes were the diagnoses of CRC and noncolorectal GI cancer. The association between BMI and cancer (CRC and noncolorectal GI cancer) was assessed using Cox proportional hazards regression modeling. The association between cancer risk and change in BMI was further analyzed at different ages, and an exploratory analysis was performed to evaluate GI cancer risk among aspirin users. Results This analysis included 135 161 participants (median [range] age, 62 [55-78] years; 67 643 [50.0%] female). Overweight BMI in early adulthood (hazard ratio [HR], 1.23; 95% CI, 1.10-1.37) and overweight BMI in middle adulthood (HR, 1.23; 95% CI, 1.13-1.34) and later adulthood (HR, 1.21; 95% CI, 1.10-1.32) as well as obese BMI in middle adulthood (HR, 1.55; 95% CI, 1.38-1.75) and later adulthood (HR, 1.39; 95% CI, 1.25-1.54) were associated with increased risk of CRC. Similar results were observed for the association with overall GI and non-CRC GI risk and BMI in middle and later adulthood. Maintaining overweight or obese BMI or increasing BMI to overweight or obese in later adulthood was also associated with increased CRC risk. Aspirin use 3 or more times per week did not significantly modify this association. Conclusions and Relevance In this secondary analysis of the PLCO Cancer Screening Trial, overweight and obese BMI in early and middle adulthood was associated with an elevated risk of CRC and noncolorectal GI cancers. The results of the current study prompt further exploration into the mechanistic role of obese BMI in carcinogenesis.
Associations Between Symptoms of Premenstrual Disorders and Polygenic Liability for Major Psychiatric Disorders
Authors: Piotr Jaholkowski, Alexey A. Shadrin, Andreas Jangmo, Evgeniia Frei, Markos Tesfaye, Guy F. L. Hindley, Marit Haram, Zillur Rahman, Lavinia Athanasiu, Nora Refsum Bakken, Børge Holen, Vera Fominykh, Gleda Kutrolli, Pravesh Parekh, Nadine Parker, Linn Rødevand, Viktoria Birkenæs, Srdjan Djurovic, Oleksandr Frei, Kevin S. O’Connell, Olav B. Smeland, Martin Tesli, Ole A. Andreassen
Journal: JAMA Psychiatry (2023)

Premenstrual disorders are heritable, clinically heterogenous, with a range of affective spectrum comorbidities. It is unclear whether genetic predispositions to affective spectrum disorders or other major psychiatric disorders are associated with symptoms of premenstrual disorders.
Letter from the journal: Improving diagnostic acumen and patient outcomes
Authors: Dirk M. Elston, Jane M. Grant-Kels, Nikki A. Levin, Murad Alam, Robert T. Brodell, Anthony P. Fernandez, Alexandra Flamm, M. Yadira Hurley, Desiree Ratner, Julie V. Schaffer, Klint Peebles, Andrew F. Alexis, Alaina J. James
Journal: Journal of the American Academy of Dermatology (2023)